Metastatic melanoma is almost always fatal, with an estimated median survival of 6-9 months and a 5-year survival rate of less than 5%. Standard systemic therapy for patients with advanced melanoma induces objective clinical responses in only 10-17% of patients. Most of these responses are not sustained, and the agents utilized (high-dose IL-2, dacarbazine) are associated with significant toxicity. Treatment alternatives that elicit comparable or improved response rates with less toxicity would represent significant advance in the therapy of late stage melanoma. Promising cancer treatment options include those that more directly target the tumor and the molecular changes that underlie malignant behavior than do conventional chemotherapy agents. In the case of melanoma, these options include molecules known to play a key role in melanoma progression and metastasis (e.g. vascular endothelial growth factor) and molecules that target cell signaling pathways that appear to be critical in the pathogenesis of this disease (e.g. PI3K/Akt/mTOR pathway). These agents, individually and together, may have immune modulating effects that could have clinical impact. This study will evaluate the effects of the anti-VEGF antibody, bevacizumab, combined with the mTOR inhibitor, CCI-779, in patients with advanced melanoma, in a multicenter clinical trial in the Molecular Targeted Combinations Correlative Study Initiative. The primary endpoint of this trial is clinical tumor response. Also, integral to this study is the evaluation of tumor tissue and peripheral blood mononuclear cells for molecular and immunologic endpoints. The effects of bevacizumab combined with CCI-779 will be evaluated under the following specific aims: Aim 1: Determine whether combination therapy with CCI-779 and bevacizumab will induce regression of metastatic melanoma (Stage III-IV); Aim 2: Determine the effects of CCI-779 and bevacizumab on circulating immune cell subsets; Aim 3: Determine the effects of CCI-779 alone and of CCI- 779 plus bevacizumab on signaling in the mTOR and VEGF pathways, both in the blood and in tumor biopsies; Aim 4: Determine whether CCI-779 alone and in combination with bevacizumab will affect signaling in parallel pathways, specifically MAPK and eNOS pathways. Approximately 1 in 70 individuals will be diagnosed with melanoma during their lifetime, and the incidence of cutaneous melanoma is on the rise. Standard systemic therapy for patients with advanced melanoma induces objective clinical responses in only 10-17% of patients and is associated with significant toxicities. The following proposal is a clinical trial to evaluate the effects of bevacizumab and CCI-779, which interfere with vascularization and tumor growth, for the treatment of melanoma. [unreadable] [unreadable] [unreadable]